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Originally published In Press as doi:10.1074/jbc.M000301200 on March 31, 2000

J. Biol. Chem., Vol. 275, Issue 22, 16899-16903, June 2, 2000
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Superoxide Production and Reactive Oxygen Species Signaling by Endothelial Nitric-oxide Synthase*

Weihan Wang, Shuibang Wang, Liang YanDagger , Patricia Madara, Ana Del Pilar Cintron, Robert A. Wesley, and Robert L. Danner§

From the Critical Care Medicine Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892

Reactive oxygen species can function as intracellular messengers, but linking these signaling events with specific enzymes has been difficult. Purified endothelial nitric-oxide synthase (eNOS) can generate superoxide (O&cjs1138;2) under special conditions but is only known to participate in cell signaling through NO. Here we show that eNOS regulates tumor necrosis factor alpha  (TNFalpha ) through a mechanism dependent on the production of O&cjs1138;2 and completely independent of NO. Expression of eNOS in transfected U937 cells increased phorbol 12-myristate 13-acetate-induced TNFalpha promoter activity and TNFalpha production. Nomega -Methyl-L-arginine, an inhibitor of eNOS that blocks NO production but not its NADPH oxidase activity, did not prevent TNFalpha up-regulation. Likewise, Gln361eNOS, a competent NADPH oxidase that lacks NOS activity, retained the ability to increase TNFalpha . Similar to the effect of eNOS, a O&cjs1138;2 donor dose-dependently increased TNFalpha production in differentiated U937 cells. In contrast, cotransfection of superoxide dismutase with eNOS prevented TNFalpha up-regulation, as did partial deletion of the eNOS NADPH binding site, a mutation associated with loss of O&cjs1138;2 production. Thus, eNOS may straddle a bifurcating pathway that can lead to the formation of either NO or O&cjs1138;2, interrelated but often opposing free radical messengers. This arrangement has possible implications for atherosclerosis and septic shock where endothelial dysfunction results from imbalances in NO and O&cjs1138;2 production.

* This work was supported by intramural National Institutes of Health funds.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: Dept. of Pathophysiology, Medical School of Jinan University, Guangzhou 510632, People's Republic of China.

§ To whom correspondence should be addressed: Critical Care Medicine Dept. NIH, Bldg. 10, Rm. 7D43, 10 Center Dr., MSC 1662, Bethesda, MD 20892-1662. Tel.: 301-496-9320; Fax: 301-402-1213; E-mail: rdanner@nih.gov.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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